tbuckley/cabot-search huggingface dataset:
Abstract 5087: <i>KDR</i> mutation as novel biomarker for immune checkpoint inhibitors in pan-cancer
Authors: Renhua Guo, Yanan Cui, Pengpeng Zhang, Xiao Liang, Jiali Xu, Xinyin Liu, Yuemin Wu, Wei Wang, Fang Zhang, Junling Zhang, Mengli Huang
Journal: Cancer Research (2022)

Abstract Purpose: Immune Checkpoint Inhibitors (ICIs) have marked important milestones in cancer treatment, while few patients experience clinical benefits from them. Therefore, reliable predictive markers for ICIs are urgently needed. Nowadays, the combination of antiangiogenic therapy and ICIs exhibits encouraging efficacy. As a key protein of VEGFR signaling, KDR may also function to regulate immune responses beyond its role in angiogenesis. Experimental Design: Pan-cancer immunotherapeutic patients from public cohorts including genomic data and clinical data were analyzed. Further analysis was performed on an internal validation data set including 67 non-small cell lung cancer (NSCLC). Investigation on underlying mechanism was performed in The Cancer Genome Atlas (TCGA) data via bioinformatics analysis. Results: We found better responses to ICIs in patients who harbored KDR mutation from pan-cancer public datasets (discovery cohort: n=662; validation cohort: n=1333). Our NSCLC cohort verified the value of KDR mutation in predicting better ICI outcomes, including objective response rate (70.0% vs 22.81%, P=0.0057) and progression-free survival (HR=0.158, 95% CI, 0.045-0.773; P=0.007). KDR mutation was associated with increased TMB level, neoantigen burden, immune cellular activities, and decreased VEGFR signaling. Meanwhile, KDR mutation was indicative of an immune-hot status, characterized by higher expression of PD-L1 and abundance of cytotoxic lymphocytes. Conclusions: Our work demonstrates that KDR mutation has the potential to become a predictive biomarker for ICIs. Citation Format: Renhua Guo, Yanan Cui, Pengpeng Zhang, Xiao Liang, Jiali Xu, Xinyin Liu, Yuemin Wu, Wei Wang, Fang Zhang, Junling Zhang, Mengli Huang. KDR mutation as novel biomarker for immune checkpoint inhibitors in pan-cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5087.
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Journal: JAMA Network Open (2022)

Nicholas H. Chakiryan, MD; L. Robert Gore, PhD; Richard R. Reich, PhD; Rodney L. Dunn, MS; Da David Jiang, MD; Kyle A. Gillis, MD; Elizabeth Green, MD; Ali Hajiran, MD; Lee Hugar, MD; Logan Zemp, MD; Jingsong Zhang, MD; Rohit K. Jain, MD; Jad Chahoud, MD; Philippe E. Spiess, MD; Brandon J. Manley, MD; Wade J. Sexton, MD; Brent K. Hollenbeck, MD; Scott M. Gilbert, MD
Abstract 5338: Pamiparib as a non-P-glycoprotein substrate PARP inhibitor can overcome <i>ABCB1</i>-mediated multidrug resistance in ovarian cancer cells
Authors: Minjuan Deng, Kang Qin, Yang Li, Yu Jiang, Wei Jin, Zhirong Shen
Journal: Cancer Research (2022)

Abstract Ovarian cancer is commonly treated with debulking surgery followed by platinum-taxane based chemotherapy and targeted therapy (PARP inhibitors). However, a key challenge facing these therapies is drug resistance caused by various mechanisms, one of which is the P-glycoprotein (P-gp, encoded by the ABCB1 gene) mediated multidrug resistance. Tumor cells with high P-gp protein expression extrude P-gp substrate drugs from intracellular space and reduce drug efficacy. Since Paclitaxel and some PARP inhibitors such as Olaparib are P-gp substrates, their clinical benefit may be compromised in primary or acquired P-gp positive patients. Pamiparib, on the other hand, is PARP inhibitor that is not P-gp substrate, therefore, it is reasonable to hypothesize that Pamiparib will have better efficacy in P-gp high ovarian tumors. To test this hypothesis, Paclitaxel or Olaparib acquired resistant cell lines were developed through prolonged in vitro culture of sensitive A2780 cells (P-gp negative) with stepwise increased concentrations of individual drug. Both Paclitaxel and Olaparib resistant cells (A2780pacR and A2780olaR, respectively) highly express P-gp protein and are cross-resistant to each other, indicating this acquired resistance is mediated by P-gp protein upregulation. Indeed, P-gp protein inhibitor Verapamil can largely restore sensitivity to Paclitaxel and Olaparib in A2780pacR and A2780olaR cells, while over-expression of P-gp protein into parental A2780 cell line recapitulated the resistant phenotype. In contrast to Paclitaxel and Olaparib, Pamiparib as non P-gp substrate, is equally sensitive to parental A2780, A2780pacR and A2780olaR cell lines and not affected by P-gp expression. Consistently, intracellular drug concentration of Pamiparib is equivalent in A2780 and A2780olaR cells, however, decreased cellular Olaparib was detected in resistant cell line. These findings have been further confirmed in Olaparib resistant CDX model, in which Pamiparib showed tumor growth inhibition while Olaparib did not. The results highly suggest that Pamiparib as a non-P-gp substrate PARP inhibitor can overcome ABCB1-mediated drug resistance in tumors and may provide additional clinical benefits to ovarian cancer patients. Citation Format: Minjuan Deng, Kang Qin, Yang Li, Yu Jiang, Wei Jin, Zhirong Shen. Pamiparib as a non-P-glycoprotein substrate PARP inhibitor can overcome ABCB1-mediated multidrug resistance in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5338.
Abstract 1787: Statin therapy enhances the efficacy of HER2 directed antibody-drug conjugates in breast cancer
Authors: Bo Liu, Joshua Z. Drago, Yi Rao, Patricia R. Pereira, Anton Safonov, Antonio Marra, Mehnaj S. Ahmed, Shanu Modi, Jorge S. Reis-Filho, Filippo Montemurro, Pedram Razavi, Jason S. Lewis, Sarat Chandarlapaty
Journal: Cancer Research (2022)

Abstract Antibody-drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER2) are a widely successful strategy for the treatment of HER2-positive breast cancer. Despite the demonstrated efficacy, intrinsic and acquired resistance to anti-HER2 ADCs remains a major challenge. The activity of ADCs is dependent upon the internalization of the HER2-ADC complex into specific subcellular compartments permissive for release of the chemotherapeutic payload. Previous studies have demonstrated that statins, a commonly used cholesterol-lowering medication, could increase plasma membrane-bound HER2 and improve trastuzumab efficacy in HER2-positive gastric cancer. In this study, we sought to characterize the impact of statins on the efficacy of HER2 ADCs. We performed in vitro internalization assays with trastuzumab emtansine (T-DM1) labeled with a pH-sensitive pHrodo fluorogenic dye to monitor T-DM1 entering lysosome whereupon payload DM1 is released, and found that combined treatment of T-DM1 and lovastatin potently enhanced T-DM1 internalization of T-DM1 into lysosome in HER2-amplified and HER2-low models. Consistent with the internalization assays, lovastatin increased cell death caused by T-DM1 and sensitized the HER2-low ZR75-1 cells to T-DM1 treatment in vitro. Using HER2-positive xenograft models, we found orally administrated lovastatin promoted T-DM1 uptake in tumors and enhanced T-DM1 efficacy in vivo. To investigate whether these results might be observed in the clinic, we conducted retrospective analyses on a cohort of 164 HER2 positive metastatic breast cancer patients treated at MSKCC who received T-DM1. Among these patients, 21 (12.8%) were taking statins concurrently with T-DM1, and the median progression-free survival in the patients who received statins was 14 months (95% confidence interval, 3.5-24 months) compared to 5.4 months (95% confidence interval, 3.9-7.0 months) in those who had no record of statin use (p=0.1). Overall, our findings demonstrate that statins potentiate the susceptibility of breast cancer cells to anti-HER2 ADCs by modulating HER2 membrane dynamics and HER2-ADC internalization, suggesting statin as a rational therapeutic partner for anti-HER2 ADC in HER2-positive breast cancer, especially those with relatively low HER2 expression. Citation Format: Bo Liu, Joshua Z. Drago, Yi Rao, Patricia R. Pereira, Anton Safonov, Antonio Marra, Mehnaj S. Ahmed, Shanu Modi, Jorge S. Reis-Filho, Filippo Montemurro, Pedram Razavi, Jason S. Lewis, Sarat Chandarlapaty. Statin therapy enhances the efficacy of HER2 directed antibody-drug conjugates in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1787.
Abstract 3765: Epigenomics at the speed of sound: High throughput epigenomic mapping of low cell input samples using acoustic enhanced immunoprecipitation
Authors: Besmira Alija, Stephanie Braunstein, Jane Xu, Tom O'Hare, Angela Garding, Aaron Viny
Journal: Cancer Research (2022)

Abstract Mapping the epigenetic landscape of Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) is essential for understanding gene regulatory mechanisms during cell fate changes, disease onset, progression, as well as for optimizing therapeutic regime. In addition, these information hold immense potential for accurate identification of disease biomarkers, cell of origin, and targets for epigenetic therapy. However, existing chromatin immunoprecipitation sequencing (ChIP-Seq) workflows require significant cellular material and are very time-consuming, requiring cumbersome optimization. Moreover, cellular heterogeneity can influence the accuracy of results from the perspective of sample preparation efficiency and also population-biased effects. Both normal and malignant bone marrow are heterogeneous in cell type and stage of differentiation that leads to imprecise results with regard to epigenetic determinates.In our study, we implemented Covaris’ Adaptive Focused Acoustics® (AFA®) technology to miniaturize sample volumes for both chromatin shearing and immunoprecipitation in a 96-well format. This approach enables a standardized, robust, automatable, half-day workflow for both ChIP and Hi-ChIP applications. Additionally, we evaluated low input in vitro and in vivo samples, where we utilized a range of epitopes including major histone modifications (H3K27ac) and factors (CTCF). AFA was applied to flow-sorted stem and progenitor populations from individual mice. The low cell input capability permitted deconvolution of dynamic epigenetic changes in protein binding and chromatin structure during normal lineage specification of hematopoietic stem cells. Epigenetic remodeling of these sites were consistent with established gene programs essential for myeloid differentiation. Data were found to be in alignment with standard ChIP-seq and Hi-C datasets generated from similar cell populations.The simplified and significantly shortened (Hi)ChIP-seq processes showcased in this study will be highly beneficial for both research and clinical diagnostic applications owing to their requirements for using 96-well plate format and their ability to become integrated into automated workflows. Taken together, this technology and workflow represent a high throughput epigenetic system for small cell numbers of cells with a multitude of applications enabling laboratories focused on cell biology and translational research. Citation Format: Besmira Alija, Stephanie Braunstein, Jane Xu, Tom O'Hare, Angela Garding, Aaron Viny. Epigenomics at the speed of sound: High throughput epigenomic mapping of low cell input samples using acoustic enhanced immunoprecipitation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3765.
Abstract 4039: Cadmium modulates steatosis, fibrogenesis, and oncogenic signaling in hepatocellular carcinoma cells through activation of Notch/AKT/mTOR pathways
Authors: Suryakant Niture, Sashi Gadi, Minghui Lin, Qi Qi, John T. Moore, Deepak Kumar
Journal: Cancer Research (2022)

Abstract Cadmium (Cd) is an environmental pollutant that increases hepatotoxicity and the risk of liver diseases. In the current study, we investigated the effect of a physiologically relevant, low concentration of Cd on the regulation of liver cancer cell proliferation, steatosis, and fibrogenic/oncogenic signaling. Exposure of Cd (1 to 10 nM) increased endogenous reactive oxygen species (ROS) production and enhanced cell proliferation in non-tumor derived HepaRG liver cells and in hepatocellular carcinoma (HCC) cell lines. Exposure of Cd increased Jagged1 expression and activated Notch signaling in HepaRG and HCC cell lines. Cd activated AKT/mTOR signaling by increasing phosphorylation of AKT-S473 and mTOR-S-4448 residues. Moreover, a low concentration of Cd also promoted cell steatosis and induced fibrogenic signaling in HCC cells. Similarly chronic exposure of HCC cells to a low concentration of Cd activated Notch and AKT/mTOR signaling. Further RNA seq data revealed that chronic Cd exposure modulate cell steatosis/fibrogenic gene expression that involved in fatty liver disease development. Cd induced the expression of pro-inflammatory cytokines TNFα and its downstream oncogenic protein Tumor Necrosis Factor-alpha (TNF-α)-Induced Protein 8 (TNFAIP8). Collectively our data suggest that a low concentration of Cd modulates cell steatosis and fibrogenic/oncogenic signaling in HCC by activation of Notch/AKT/mTOR pathways. Citation Format: Suryakant Niture, Sashi Gadi, Minghui Lin, Qi Qi, John T. Moore, Deepak Kumar. Cadmium modulates steatosis, fibrogenesis, and oncogenic signaling in hepatocellular carcinoma cells through activation of Notch/AKT/mTOR pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4039.
Abstract 1149: Decitabine inhibits breast cancer cell proliferation through inhibition of endogenous retroviruses in vitro
Authors: Jiayi Li, John Lin, Leo Andrada, Bryce Grohol, Serratt Nong, Yingguang Liu
Journal: Cancer Research (2022)

Abstract The purpose of the study is to elucidate the antineoplastic mechanisms of decitabine, a DNA methyltransferase inhibitor. Previous literature suggests that decitabine activates human endogenous retroviruses which subsequently enhances expression of interferons, thereby suppressing tumor cell proliferation. Contrary to this hypothesis, our in vitro study with human and mouse breast cancer cell lines showed a positive correlation between the antiproliferative effect of decitabine and its suppressive effect on two endogenous retroviruses, the human endogenous retrovirus type K (HERV-K) and the mouse mammary tumor virus (MMTV). Decitabine stimulated proliferation of the T47D human breast cancer cell line at lower doses but inhibited cell proliferation at higher doses. Correspondingly, HERV-K transcripts (env and pol) increased at lower doses and decreased at higher doses. Interestingly, expression of the E-cadherin gene, an indicator of epithelial differentiation, followed an opposite trend. Decitabine inhibited proliferation of the mouse 4T1 breast cancer cell line and its expression of MMTV in a dose-dependent manner, while enhancing expression of the mouse E-cadherin. 4T1 cells overexpressing MMTV env became more resistant to decitabine, so was a human breast cancer cell line (BT-20) overexpressing HERV-K env, while T47D cells with HERV-K knockdown became more susceptible to the drug. Meanwhile, in vivo studies showed that decitabine successfully suppressed tumor development in BALB/c mice inoculated with 4T1 cells. Surprisingly, expression of MMTV env was elevated in tumors of mice treated with decitabine, along with enhanced E-cadherin expression. These data suggest decitabine inhibits cancer cell proliferation (at least partially) through inhibition of endogenous retroviruses in vitro, but its mechanisms of action in vivo are different. Further studies of the interaction between decitabine and endogenous retroviruses using engineered 4T1 cells in BALB/c mice are currently underway. Citation Format: Jiayi Li, John Lin, Leo Andrada, Bryce Grohol, Serratt Nong, Yingguang Liu. Decitabine inhibits breast cancer cell proliferation through inhibition of endogenous retroviruses in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1149.
Effect of Intraoperative Urinary Catheter Use on Postoperative Urinary Retention After Laparoscopic Inguinal Hernia Repair
Authors: Aldo Fafaj, Emanuele Lo Menzo, Diya Alaedeen, Clayton C. Petro, Steven Rosenblatt, Samuel Szomstein, Christian Massier, Ajita S. Prabhu, David M. Krpata, Walter Cha, Katherine Montelione, Luciano Tastaldi, Hemasat Alkhatib, Samuel J. Zolin, Luis Felipe Okida, Michael J. Rosen
Journal: JAMA Surgery (2022)

Urinary catheters are commonly placed during laparoscopic inguinal hernia repair as a presumed protection against postoperative urinary retention (PUR), one of the most common complications following this operation. Data from randomized clinical trials evaluating the effect of catheters on PUR are lacking.To investigate the effect of intraoperative catheters on PUR after laparoscopic inguinal hernia repair.This 2-arm registry-based single-blinded randomized clinical trial was conducted at 6 academic and community hospitals in the US from March 2019 to March 2021 with a 30-day follow-up period following surgery. All patients who presented with inguinal hernias were assessed for eligibility, 534 in total. Inclusion criteria were adult patients undergoing laparoscopic, elective, unilateral, or bilateral inguinal hernia repair. Exclusion criteria were inability to tolerate general anesthesia and failure to understand and sign the written consent form. A total of 43 patients were excluded prior to intervention.Patients in the treatment arm had placement of a urinary catheter after induction of general anesthesia and removal at the end of procedure. Those in the control arm had no urinary catheter placement.PUR rate.Of the 491 patients enrolled, 241 were randomized to catheter placement, and 250 were randomized to no catheter placement. The median (IQR) age was 61 (51-68) years, and 465 participants (94.7%) were male. Overall, 44 patients (9.1%) developed PUR. There was no difference in the rate of PUR between the catheter and no-catheter groups (23 patients [9.6%] vs 21 patients [8.5%], respectively; P = .79). There were no intraoperative bladder injuries. In the catheter group, there was 1 incident of postoperative urethral trauma in a patient who presented to the emergency department with PUR leading to a suprapubic catheter placement.Intraoperative urinary catheters did not reduce the risk of PUR after laparoscopic inguinal hernia repair. While their use did not appear to be associated with a high rate of iatrogenic complications, there may be a low rate of catastrophic complications. In patients who voided urine preoperatively, catheter placement did not appear to confer any advantage and thus their use may be reconsidered.ClinicalTrials.gov Identifier: NCT03835351.
Abstract 3877: Deep ultrahigh-plex spatial phenotyping of human cancer tissues
Authors: Niyati Jhaveri, Nadya Nikulina, Hailing Zong, Ning Ma, Bassem Ben Cheikh, Aditya Pratapa, Yasmin Kassim, Bhaskar Anand, Michael Prater, Subham Basu, Oliver Braubach
Journal: Cancer Research (2022)

Abstract Spatial phenotyping is poised to revolutionize cancer research and treatment. Technologies like CO-Detection by indEXing (CODEX), which enable the detection of dozens of protein biomarkers in situ, have already transformed immuno-oncology and are expected to play formative roles in future research. To further support the implementation of CODEX in cancer research, we present a comprehensive 100 antibody panel that is aimed at in-depth identification of immune cell lineages, activation states, immune checkpoints, tissue structure, cellular signaling, apoptosis, DNA damage and cellular metabolism. Deployment of this panel is possible at high-throughput on the CODEX platform, which is a fully-integrated spatial biology solution that provides cyclical multiplexed imaging at unprecedented resolution and rapid turn-around time. The key features of this novel spatial biology system include: 1) true single-cell and sub-cellular resolution, 2) unparalleled biomarker imaging depth on whole FFPE samples, 3) wide-ranging compatibility with whole slide FFPE tissues, 4) panel customization and flexibility via dedicated barcodes, 5) uncompromised access to whole tissues, and 6) sophisticated single-cell analytical metrics. In this study, we generate a comprehensive account of the spatial biology in different tumor tissues including lung cancer, colon cancer, and melanoma using the CODEX instrument. Single-cell spatial phenotyping coupled with deep bioinformatic analyses reveals new quantitative phenotypic and spatial information that will be essential to gain further insights into distinct cellular neighborhoods and their role in regulating immune and metabolic functions of certain cancers. Citation Format: Niyati Jhaveri, Nadya Nikulina, Hailing Zong, Ning Ma, Bassem Ben Cheikh, Aditya Pratapa, Yasmin Kassim, Bhaskar Anand, Michael Prater, Subham Basu, Oliver Braubach. Deep ultrahigh-plex spatial phenotyping of human cancer tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3877.